We infer the existence of a gene NIDDM2 causing NIDDM associated with low insulin secretion, and suggest that NIDDM2 and MODY3 may represent different alleles of the same gene.
Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1).
Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caused by mutations in the transcription factor hepatocyte nuclear factor-1alpha (HNF-1alpha) located on chromosome 12q.
MODY is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MODY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3].
A missense mutation of R272H (replacement of Arg by His in codon 272) in the DNA binding domain of HNF-1 alpha was found in a subject who developed IDDM 1 year after diagnosis of NIDDM at 8 years of age.
The HNF-1 alpha frameshift mutations were not detected in any late-onset NIDDM subjects, suggesting these mutations do not have a major role in the pathogenesis of NIDDM.
Coronary heart disease was more common in MODY3 than in IDDM (16 vs 4.5%; p < 0.02) but less common than in the older NIDDM patients (33.3%; p < 0.02).
To evaluate the role of HNF1 alpha in the more common familial type 2 diabetes, we studied 62 families of Northern European origin by linkage analysis and molecular screening.
Furthermore, the regression model indicated that the HNF1A S319 allele affected these traits in a dominant manner in subjects with and without type 2 diabetes.